The Redox Reactions Of Copper

Except for conditions of strong oxidative stress or high iron levels, the endogenous copper pool in cells and tissues is considered now as the determinant for the formation and decomposition of RS-NO in biosystems [1,3,13,20]. The redox couple Cu2+/Cu+ has a rather small redox potential Eo = +0.15 V. Therefore, in principle, copper can catalyze the decomposition of RS-NO by shuttling between its two redox states according to the reaction as in Scheme 1.

One-electron reduction of RS-NO by the monovalent Cu+ ion destabilizes the RS-NO molecule and initiates its decomposition by release of the NO moiety. Subsequent oxidation of the RS- anion by Cu2+ ion results in the release of a thiyl radical, and regeneration of copper to its original monovalent charge state. The thiyl radicals are not very reactive to other species, but easily combine by forming a covalent disulfide bond. The formation of disulfides like cysteine makes the decomposition of RS-NO irreversible. The reductive decomposition does not involve oxygen and proceeds in oxygenated as well as anoxic solutions.

In principle, the decomposition of RS-NO may be initiated by divalent copper ions. This reaction requires the presence of an oxidizer like oxygen and could proceed according to Scheme 2:

This decomposition pathway is also irreversible due to the formation of disulfides and the subsequent hydrolysis of nitrosonium NO+ to nitrite NO-.

Evidently, the oxidative mechanism of RS-NO decomposition can be dominant at high levels of oxygen in the solution. However, under normoxic physiological conditions as encountered in tissues and biological samples, the reductive mechanism seems dominant. Experiments have shown that GS-NO decomposition involves the release of NO in neutral radical state rather than nitrosonium, and that the decomposition may be inhibited by scavenging Cu+ ions with neocuproine. Both observations provide strong experimental evidence for the dominance of reductive decomposition according to Scheme 1.

The synthesis of RS-NO catalyzed by Cu2+ ions can proceed via two pathways shown in Schemes 3 and 4:

Scheme 3. The first pathway for RS-NO synthesis catalyzed by copper [11].

Second possible mechanism of RS-NO synthesis induced by Cu2+ ions is shown in Scheme 4:

Scheme 4. The second pathway for RS-NO synthesis catalyzed by copper [5,11].

Thus, the oxidative mechanisms are characteristic of RS-NO synthesis for both pathways. However, two arguments suggest that the oxidative mechanisms are not significant under physiological conditions. First, thiyl radicals as formed in Scheme 3 will react not only with free NO, but with each other (disulfide formation) as well as with other compounds. Second, in the presence of water, free nitrosonium ions as released in Scheme 4 rapidly hydrolyzed to nitrite. Therefore, nitrosonium could S-nitrosate thiol moieties only at high thiol concentrations or if strong binding with copper ions protects it against the hydrolysis.